The acute effects of ethanol are mediated by binding to specific sites on proteins. We propose to elucidate the actions of ethanol on the GABAa and glycine receptors, two critical molecular targets for ethanol, by combining molecular, electrophysiological and behavioral methods.
Aim 1 will elucidate the specific location and orientation of the amino acids that form the ethanol binding site in heteromeric GABAa receptors. Our ongoing studies of glycine receptors suggest that zinc, a physiological modulator of glycine receptors, is important for ethanol action on these receptors, and Aim 1 will also define the molecular basis of this interaction.
In Aim 2, we will use GABAa and glycine receptor knockout and knockin mice to specify the behavioral effects of ethanol that are due to actions on these receptors.
Aim 3 will evaluate the neuronal consequences of receptor mutation. This will be accomplished by genomic analysis of key brain regions and by electrophysiological study of the mesolimbic reward pathway.
Aim 3 will also define effects of chronic ethanol consumption on global gene expression changes in the ventral tegmental area and nucleus accumbens, the two key areas of the mesolimbic pathway. These studies will use wild type mice and mice with GABAa or glycine receptors that are engineered to be insensitive to ethanol action. This novel approach will allow us to link changes in gene expression (and behavior, Aim 2) to alcohol actions on specific receptors. The long-range goal of this work is to define key protein sites that can serve as targets for new therapies to alleviate alcohol reinforcement, dependence an relapse.
Even though alcohol (ethanol) has been consumed for thousands of years, we know remarkably little about the way it produces its effects on the brain. An important advance was the identification of specific proteins (neurotransmitter receptors and ion channels) involved in communication between neurons as a target for ethanol. We will define how ethanol acts on these proteins using different techniques, ranging from the molecular to the behavioral level, using mutations in mice and other new technologies, with the final objective of defining key protein sites that can serve as targets for new therapies to alleviate alcohol addiction.
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|Blednov, Yuri A; Black, Mendy; Benavidez, Jillian M et al. (2016) PPAR Agonists: I. Role of Receptor Subunits in Alcohol Consumption in Male and Female Mice. Alcohol Clin Exp Res 40:553-62|
|Mayfield, J; Arends, M A; Harris, R A et al. (2016) Genes and Alcohol Consumption: Studies with Mutant Mice. Int Rev Neurobiol 126:293-355|
|Borghese, Cecilia M; Ruiz, Carlos I; Lee, Ui S et al. (2016) Identification of an Inhibitory Alcohol Binding Site in GABAA Ï1 Receptors. ACS Chem Neurosci 7:100-8|
|Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy et al. (2015) Role of interleukin-1 receptor signaling in the behavioral effects of ethanol and benzodiazepines. Neuropharmacology 95:309-20|
|Bajo, M; Herman, M A; Varodayan, F P et al. (2015) Role of the IL-1 receptor antagonist in ethanol-induced regulation of GABAergic transmission in the central amygdala. Brain Behav Immun 45:189-97|
|Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy et al. (2015) Glycine receptors containing Î±2 or Î±3 subunits regulate specific ethanol-mediated behaviors. J Pharmacol Exp Ther 353:181-91|
|Mayfield, Jody; Blednov, Yuri A; Harris, R Adron (2015) Behavioral and Genetic Evidence for GIRK Channels in the CNS: Role in Physiology, Pathophysiology, and Drug Addiction. Int Rev Neurobiol 123:279-313|
|Borghese, Cecilia M (2015) The molecular pharmacology of volatile anesthetics. Int Anesthesiol Clin 53:28-39|
|Horani, Suzzane; Stater, Evan P; Corringer, Pierre-Jean et al. (2015) Ethanol Modulation is Quantitatively Determined by the Transmembrane Domain of Human Î±1 Glycine Receptors. Alcohol Clin Exp Res 39:962-8|
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